The sanctuary for HIV-1 in the brain is formed by maintenance of virus in long-lived macrophages and microglia within the confines of the blood-brain barrier. This chronic productive infection stands in contrast to the productive form of infection in lymphocytes which is short lived and highly sensitive to antiviral intervention. The effects of antiviral therapy upon chronic infection in the brain and on the synthesis of viral and cellular neurotoxins have not been fully defined. Productive HIV of macrophage is known to activate synthesis of neurotoxin. We hypothesize that interactions of HIV-1 with macrophages which do not result in the production of infectious progeny virus, including viral replication in chronically infected cells in the presence of antiviral drugs, also induce neurotoxicity. We particularly wish to distinguish transient events driven by the interactions between viral envelope and CXCR4 or CCR5 from those arising from chronic infection in a potential viral reservoir in HIV-1 infected macrophages. The Specific Aims are: 1. To determine the virological characteristics of the reservoir established in macrophages during chronic productive or controlled HIV-1 infection; 2. To correlate the production of neurotoxins with the expression and control of HIV-i in chronically infected macrophages. 3. To determine the ability of ligands of CCR5 or CXCR4 to activate macrophages to neurotoxin synthesis. 4. To determine the minimal interaction of HIV-1 with macrophages which activate cells to induce apoptosis in neurons. Experiments will be conducted exclusively with primary monocyte-derived macrophages. We shall monitor viral replication by PCR, Western blot, and specific immunoassays. HIV-1 infection will be arrested using viral mutants or inhibitors of reverse transcription, Tat or protease activity. Soluble neurotxins will be measured by assay of direct neuronal killing and by apoptosis in the laboratory of Dr. Gelbard and by immunoassay and Western blot. Ligation of chemokine receptors will be measured by Ca++ assays.